Establishment of a transgenic monkey of Huntingtons's diesease

描述（由申请人提供）：非人灵长类动物（NHP;猴子）在生物医学研究的许多领域做出了重大贡献，因为它们是研究人类疾病的宝贵模型。转基因技术的最新进展导致了第一个亨廷顿病（HD）转基因猴模型的建立。转基因HD猴出现与人类患者相似的神经病理学，这在啮齿动物模型中很少观察到。除了突变亨廷顿蛋白（htt）对猴子的神经毒性外，HD猴子还出现与HD患者相似的不自主运动和协调身体运动的困难。我们已经成功地实现了我们的目标，在开发一个转基因HD猴，表达突变htt和发展的症状与人类患者相当的原始应用。我们总共培育了五只足月出生的转基因猴子，它们都是带有突变htt和绿色荧光蛋白基因的双转基因猴子。三只HD猴幼崽表现出严重的舞蹈病和肌张力障碍体征。两个存活了一天，第三个存活了一个月。其临床症状和疾病严重程度的变化表明CAG重复序列的数量、整合事件的数量和htt片段的大小的影响。我们的目标是继续表征现有的两只HD猴（目前为10个月大）和新一代HD猴（预计在母申请的最后一个预算年度）。因此，将建立HD猴创始者队列。本申请旨在继续监测HD猴队列中的疾病发展，并通过非侵入性成像和认知行为测试监测HD进展。本申请的主要目标是对HD猴进行深入表征，并建立一个具有已知基因型和表型的HD猴队列。我们将评价HD猴模型是否是比啮齿动物模型更好的再现人类HD的模型。我们还制定了建立HD猴子队列的计划，这些猴子将可用于HD研究社区。我们的三个具体目标是：（1）转基因HD猴的表型特征评估，（2）转基因HD猴的分子和细胞特征评估，以及（3）HD猴精子和胚胎的冷冻保存。相关性（参见说明）：本研究将继续表征转基因HD猴，并确定与其他动物模型相比，转基因猴模型是否具有建模人类遗传性神经退行性疾病的特权。还制定了一项战略计划，以建立一个HD猴队列，供HD研究界使用。

DESCRIPTION (provided by applicant): Nonhuman primates (NHPs; monkeys) have contributed significantly in many areas of biomedical research as they are invaluable models for studying human diseases. Recent advancements in transgenic technology have resulted in the creation of the first transgenic monkey model of Huntington's disease (HD). Transgenic HD monkeys develop neuropathologies similar to that of human patients, which are rarely observed in rodent models. Besides the neurotoxicity of mutant huntingtin (htt) in monkeys, HD monkeys also develop involuntary movement and difficulties in coordinating body movement similar to that of HD patients. We have successfully accomplished our goal of the original application in developing a transgenic HD monkey that expresses mutant htt and develops symptoms comparable to human patients. We have generated a total of five transgenic monkeys that were born at full term and they were all double transgenic with mutant htt and green fluorescent protein genes. Three of the HD monkey infants exhibited severe signs of chorea and dystonia. Two survived for one day and the third for one month. The variations in their clinical symptoms and the severity of the disease suggest the effect of the number of CAG repeats, the number of integration events, and the size of the htt fragment. Our objective is to continue characterizing the two existing HD monkeys, currently ten months old, and the new generation of HD monkeys that are expected in the last budgeted year of the parent application. Thus a cohort of HD monkey founders will be established. This application aims to continue monitoring disease development among the cohort of HD monkeys and monitoring HD progression by non-invasive imaging and cognitive behavioral tests. The primary goals of this application are to perform in-depth characterization on HD monkeys and establish a cohort of HD monkeys with known genotypes and phenotypes. We will evaluate if the HD monkey model is a better model to recapitulate HD in humans than a rodent model. We have also laid out a plan for establishing a cohort of HD monkeys, which will be available for the HD research community. Our three specific aims are: (1) Assessment of phenotypic characteristics in transgenic HD monkeys, (2) Assessment of molecular and cellular characteristics in transgenic HD monkeys, and (3) Cryopreservation of HD monkey's spermatozoa and embryos. RELEVANCE (See instructions): This study is to continue characterizing transgenic HD monkeys and determines if a transgenic monkey model has privileged of modeling human inherited neurodegenerative diseases compared to the other animal models. A strategic plan is also developed for the establishment of a cohort of the HD monkey, which will be available for the HD research community.